The role interplay between mesoporous silica pore volume and surface area and their effect on drug loading capacity.

In this study, the influence of the mesoporous silica (MS) textural properties (surface area, pore diameter, and pore volume) on drug loading capacity (monomolecular loading capacity and pore filling capacity) was investigated theoretically and experimentally using a thermoanalytical method. The loading capacities of three model drugs (celecoxib, cinnarizine, and paracetamol) were determined in five different MS grades of Sylysia® with identical chemical composition, but varying surface area, pore diameter and pore volume. The experimentally determined loading capacities were compared to theoretical loading capacities, calculated based on the surface area and amorphous density of the drugs, and the surface area and pore volume of the MS. The findings of the study showed that the monomolecular loading capacity generally increased with increasing surface area and decreasing pore volume of the MS. However, the MS grade with the highest surface area did not display the highest monomolecular loading capacity for any of the three drugs. This was probably a result of the decreasing pore diameter necessary to accommodate the increasing surface area of the MS i.e., if the pore is smaller than the drug molecule, the drug cannot access the available surface area. For these systems, the amorphous density of the drug and the pore volume of the MS was used to estimate the theoretical pore filling capacity, which was in good agreement with the experimentally determined loading capacity. In conclusion, this study showed that both the pore volume and surface area of the MS will have an influence on the drug loading capacity and that this can be estimated with good accuracy both theoretically and experimentally.

Characterization of the Hydrodynamics in a Miniaturized Dissolution Apparatus.

The hydrodynamics of a miniaturized dissolution apparatus was characterized using computational fluid dynamics simulations and analyzed in relation to the biorelevance and robustness of measurements of drug dissolution and precipitation kinetics from supersaturated drug solutions. The effect of using 3 different agitator geometries operated at 50, 100, 150, and 200 rpm as well as different positioning of an UV probe in the vessel was systematically evaluated. The computational fluid dynamics simulations were validated using a particle streak velocimetry experiment. The results show that the choice of agitator geometry influences the hydrodynamics of the system and indicates that an off-center probe position may result in more robust measurements. Furthermore, the study shows that the agitator geometry has a significant effect on supersaturation studies due to differences in the hydrodynamic shear produced by the agitator.

Investigation of the Intra- and Interlaboratory Reproducibility of a Small Scale Standardized Supersaturation and Precipitation Method.

The high number of poorly water-soluble compounds in drug development has increased the need for enabling formulations to improve oral bioavailability. One frequently applied approach is to induce supersaturation at the absorptive site, e.g., the small intestine, increasing the amount of dissolved compound available for absorption. However, due to the stochastic nature of nucleation, supersaturating drug delivery systems may lead to inter- and intrapersonal variability. The ability to define a feasible range with respect to the supersaturation level is a crucial factor for a successful formulation. Therefore, an in vitro method is needed, from where the ability of a compound to supersaturate can be defined in a reproducible way. Hence, this study investigates the reproducibility of an in vitro small scale standardized supersaturation and precipitation method (SSPM). First an intralaboratory reproducibility study of felodipine was conducted, after which seven partners contributed with data for three model compounds; aprepitant, felodipine, and fenofibrate, to determine the interlaboratory reproducibility of the SSPM. The first part of the SSPM determines the apparent degrees of supersaturation (aDS) to investigate for each compound. Each partner independently determined the maximum possible aDS and induced 100, 87.5, 75, and 50% of their determined maximum possible aDS in the SSPM. The concentration-time profile of the supersaturation and following precipitation was obtained in order to determine the induction time (tind) for detectable precipitation. The data showed that the absolute values of tind and aDS were not directly comparable between partners, however, upon linearization of the data a reproducible rank ordering of the three model compounds was obtained based on the ß-value, which was defined as the slope of the ln(tind) versus ln(aDS)-2 plot. Linear regression of this plot showed that aprepitant had the highest ß-value, 15.1, while felodipine and fenofibrate had comparable ß-values, 4.0 and 4.3, respectively. Of the five partners contributing with full data sets, 80% could obtain the same rank order for the three model compounds using the SSPM (aprepitant > felodipine ≈ fenofibrate). The α-value is dependent on the experimental setup and can be used as a parameter to evaluate the uniformity of the data set. This study indicated that the SSPM was able to obtain the same rank order of the ß-value between partners and, thus, that the SSPM may be used to classify compounds depending on their supersaturation propensity.

Adjuvants Based on Synthetic Mycobacterial Cord Factor Analogues: Biophysical Properties of Neat Glycolipids and Nanoself-Assemblies with DDA.

Synthetic mycobacterial cord factor analogues, e.g., trehalose 6,6'-dibehenate (TDB), are highly promising adjuvants due to their strong immunopotentiating capabilities, but their biophysical properties have remained poorly characterized. Here, we report the synthesis of an array of synthetic TDB analogues varying in acyl chain length, degree of acylation, and headgroup display, which was subjected to biophysical characterization of neat nondispersed self-assembled nanostructures in excess buffer and as aqueous dispersions with cationic dimethyldioctadecylammonium (DDA) bromide. The array comprised trehalose mono- (TMX) and diester (TDX) analogues with symmetrically shortened acyl chains [denoted by X: arachidate (A), stearate (S), palmitate (P), myristate (Myr), and laurate (L)] and an analogue with a short hydrophilic polyethylene glycol (PEG) linker inserted between the trehalose headgroup of TDS and the acyl chains (PEG-TDS). All dispersions were liposomes, but in contrast to the colloidally stable and highly cationic TDX-containing liposomes, the zeta-potential was significantly reduced for DDA/TMX and DDA/PEG-TDS liposomes, suggesting a charge-shielding effect, which compromises the colloidal stability. An increased d-spacing was observed for the lamellar phase of neat TDB analogues in excess buffer (TDS < TMS < PEG-TDS), confirming that the charge shielding is caused by an extended molecular configuration of the more flexible headgroup. Differential scanning calorimetry showed highly cooperative phase transitions for all tested dispersions albeit the monoesters destabilized the lipid bilayers. Langmuir experiments demonstrated that incorporation of TDXs and PEG-TDS stabilized DDA monolayers due to improved hydrogen bonding and reduced intermolecular repulsions. In conclusion, data suggest that the DDA/TDS dispersions exhibit favorable physicochemical properties rendering these DDA/TDS liposomes an attractive vaccine adjuvant, and they emphasize that not only the receptor binding and immune activation but also the biophysical properties of immunopotentiator formulations should be collectively considered when designing adjuvants with optimal safety, efficacy, and storage stability.